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Synthesis and Pharmacological Evaluation of 5‑Pyrrolidinylquinoxalines as a Novel Class of Peripherally Restricted κ‑Opioid Receptor Agonists
5-Pyrrolidinyl
substituted perhydroquinoxalines were designed as
conformationally restricted κ-opioid receptor agonists restricted
to the periphery. The additional N atom of the quinoxaline system
located outside the ethylenediamine κ pharmacophore allows the
fine-tuning of the pharmacodynamic and pharmacokinetic properties.
The perhydroquinoxalines were synthesized stereoselectively using
the concept of late stage diversification of the central building
blocks <b>14</b>. In addition to high κ-opioid receptor
affinity they demonstrate high selectivity over μ, δ,
σ<sub>1</sub>, σ<sub>2</sub>, and NMDA receptors. In the
[<sup>35</sup>S]GTPγS assay full agonism was observed. Because
of their high polarity, the secondary amines <b>14a</b> (log <i>D</i><sub>7.4</sub> = 0.26) and <b>14b</b> (log <i>D</i><sub>7.4</sub> = 0.21) did not penetrate an artificial
blood–brain barrier. <b>14b</b> was able to inhibit the
spontaneous pain reaction after rectal mustard oil application to
mice (ED<sub>50</sub> = 2.35 mg/kg). This analgesic effect is attributed
to activation of peripherally located κ receptors, since <b>14b</b> did not affect centrally mediated referred allodynia and
hyperalgesia